HEMOGLOBINOPATHIES

• Hemoglobinopathy refers to a disease state (opathy) involving the hemoglobin (Hb) molecule
• Hemoglobinopathies are the most common genetic diseases, affecting approximately 7% of the world's population
• More than 300,000 children are born each year with some form of inherited hemoglobin disorder and approximately 80% occur in mid- to low-income countries
• All hemoglobinopathies result from a genetic mutation in one or more genes that affect hemoglobin synthesis
• Qualitative hemoglobinopathies


  Hemoglobin synthesis occurs at a normal or near-normal rate, but the hemoglobin molecule has an altered amino acid sequence within the globin chains
• Thalassemias


  Result in a reduced rate of hemoglobin synthesis (quantitative) but do not affect the amino acid sequence of the affected globin chains
• Types of hemoglobinopathies


  • Structural defects (qualitative)
  • Thalassemias (quantitative)
• There are six functional human globin genes located on two different chromosomes
• Two of the globin genes, a and (, are located on chromosome 16 and are referred to as a-like genes
• The remaining four globin genes, ẞ, y, d, and e, are located on chromosome 11 and are referred to as ẞ-like genes
• Each globin gene codes for the corresponding globin chain
• During the first 3 months of embryonic life, only one a-like gene (5) and one ẞ-like gene (e) are activated, which results in the production of (- and e-globin chains that pair to form hemoglobin Gower-1 (32€2)
• Shortly thereafter, a and y chain synthesis begins, which leads to the production of Hb Gower-2 (α₂€2) and Hb Portland (≤2Y2)
• Later in fetal development, ( and € synthesis ceases; this leaves a and y chains, which pair to produce Hb F (α2Y2), also known as fetal hemoglobin
• During the 6 months after birth, y chain synthesis gradually decreases and is replaced by ẞ chain synthesis so that Hb A (α2ẞ2), also known as adult hemoglobin, is produced
• BCL11A and Krüppel-like factor 1 (KLF1), zinc-finger transcriptional repressors, are necessary to silence the y-globin gene and are part of a complex mechanism involved in y-ẞ switching; mutations in the gene that codes for either factor results in elevated Hb F levels
• The remaining 8-globin gene, becomes activated around birth, producing & chains at low levels that pair with a chains to produce the second adult hemoglobin, Hb A2 (α282)
• Normal adults produce Hb A (95%), Hb A₂ (less than 3.5%), and Hb F (less than 1% to 2%)
• More than 1200 structural hemoglobin variants (hemoglobinopathies) are known to exist throughout the world, and more are being discovered regularly
• Types of genetic mutations in hemoglobinopathies

  • Point mutations
  • Deletions
  • Insertions
  • Fusions
• Point mutation


  The replacement of one original nucleotide in the normal gene with a different nucleotide
• 1178 of the 1275 known hemoglobin variants result from a point mutation that causes an amino acid substitution
• Deletions


  Involve the removal of one or more nucleotides
• Insertions


  Result in the addition of one or more nucleotides
• 58 variants result from deletions and 28 from insertions
• Chain extensions


  Occur when the stop codon is mutated so that translation continues beyond the typical last codon
• Gene fusions


  Occur when two normal genes break between nucleotides, switch positions, and anneal to the opposite gene
• Nine fusion globin chains have been identified
• Zygosity


  Refers to the association between the number of mutations and the level of severity of the resultant genetic defect
• Heterozygous


  Only one ẞ gene is mutated
• Homozygous


  Both ẞ genes are mutated
• In homozygous ẞ-hemoglobinopathies, the variant hemoglobin becomes the dominant hemoglobin type and normal hemoglobin (Hb A) is absent
• In heterozygous ẞ-hemoglobinopathies, one ẞ gene is mutated and the other is normal, which suggests a 50/50 distribution
• Patients with homozygous SCD (Hb SS) inherit a severe form of the disease that occurs less often but requires lifelong medical intervention, which must begin early in life, whereas heterozygotes (Hb AS) are much more common
• Globin crystals


  Stretch the red blood cell (RBC) membrane and produce the characteristic crescent moon or sickle cell shape
• Zygosity


  Affects the pathophysiology of the disease
• 1. hemoglobinopathies


  • Homozygous (both β genes mutated)
  • Heterozygous (one β gene mutated, one normal)
• Homozygous β-hemoglobinopathies


  Variant hemoglobin becomes the dominant hemoglobin type and normal hemoglobin (Hb A) is absent
• Homozygous β-hemoglobinopathies


  • Sickle cell disease (Hb SS)
  • Hb C disease (Hb CC)
• Heterozygous β-hemoglobinopathies


  One β gene is mutated and the other is normal, which suggests a 50/50 distribution. Variant hemoglobin is usually present in lesser amounts than Hb A.